A comment on “A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B”
Authors: Yue-Meng Wan, Hua-Mei Wu, Song-Quan Huang, Hua-Yu Li, Hong-Jing Yin
Journal: Journal of Hepatology (2023)

A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis BJournal of HepatologyVol. 78Issue 5PreviewNucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. Full-Text PDF Open AccessReply to: "A comment on `A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B'"Journal of HepatologyVol. 80Issue 5PreviewWe are pleased to receive the letter to the editor from Yue-Meng Wan and his colleagues1 regarding our recently published results from the STOP-NUC clinical trial.2 Full-Text PDF We read with interest the study by van Bömmel et al.1van Bömmel F. Stein K. Heyne R. et al.A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B.J Hepatol. 2023; 78: 926-936Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar that reported results from a prospective, randomized-controlled trial (RCT) on nucleos(t)ide analogue (NUC) cessation as a therapeutic intervention in HBeAg-negative patients with chronic hepatitis B (CHB). After a follow-up period of 96 weeks (two years), the authors demonstrated HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in arm A with NUC cessation compared to none in arm B (0%, 95% CI 0%-5.8%) with continued NUC treatment (p = 0.006). No serious adverse events related to treatment cessation occurred. Although this is an RCT, we still have the following concerns. First, the rate of HBsAg loss seems to be discrepant with previous ones. On the one hand, it seems to be much lower than that of a European study by Hadziyannis et al.,2Hadziyannis S.J. Sevastianos V. Rapti I. et al.Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.Gastroenterology. 2012; 143: 629-636.e1Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar in which a total of 3 (9.1%), 6 (18.2%), 8 (24.2%), 9 (27.3%), 10 (30.3%), and 13 (39%) of 33 patients stopping NUC treatment cleared HBsAg at 1, 2, 3, 4, 5, and 6 years, respectively. On the other hand, it seems to be obviously higher than that of a study from Hong Kong, in which only 1% (11/1,076) of patients achieved HBsAg loss after stopping NUCs at 44.3 ± 24.6 months.3Wong G.L. Chan H.L. Yuen B.W. et al.The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.Liver Int. 2020; 40: 549-557Crossref PubMed Scopus (13) Google Scholar Thus, it may be premature to draw any conclusion before these discrepant results can be explained reasonably. Second, the authors only recruited HBeAg-negative patients, even though HBeAg-positive patients may have similar outcomes. Previously, Chen et al.4Chen C.H. Hung C.H. Wang J.H. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.Clin Microbiol Infect. 2018; 24: 997-1003Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar showed that the 3- and 8-year cumulative rates of HBsAg loss were 5.2% and 19.6% in HBeAg-positive patients, and 10.5% and 33.1% in HBeAg-negative ones, respectively. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-therapy (EOT) HBsAg levels <300 IU/ml, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with EOT HBsAg levels <200 IU/ml. These data demonstrated similar outcomes at 3-8 years between HBeAg-positive and -negative patients. Thus, it seems unnecessary to exclude HBeAg-positive patients in this trial. Third, the authors did not present the baseline information about the viral genotypes of patients, which should be viewed as a limitation of this trial, since numerous studies demonstrated that viral genotype is significantly associated with HBsAg loss in patients with both HBeAg-positive and -negative CHB.4Chen C.H. Hung C.H. Wang J.H. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.Clin Microbiol Infect. 2018; 24: 997-1003Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,5Sonneveld M.J. Chiu S.M. Park J.Y. et al.Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.J Hepatol. 2022; 76: 1042-1050Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Fourth, the safety of this strategy is also a big concern. Despite no serious adverse events being recorded, virological relapse, ALT flares (35.4%) and retreatment (11.3%) are common. Regardless of prompt retreatment, hepatic decompensation (0.8% [7/914] or 1.2% [5/411]), liver failure and death (0.24% [1/411]) have been reported following NUC cessation in previous studies.3Wong G.L. Chan H.L. Yuen B.W. et al.The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.Liver Int. 2020; 40: 549-557Crossref PubMed Scopus (13) Google Scholar,4Chen C.H. Hung C.H. Wang J.H. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.Clin Microbiol Infect. 2018; 24: 997-1003Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Therefore, stopping NUCs to achieve functional cure should not be recommended at this moment.3Wong G.L. Chan H.L. Yuen B.W. et al.The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic hepatitis B.Liver Int. 2020; 40: 549-557Crossref PubMed Scopus (13) Google Scholar Above all, we congratulate Florian van Bömmel and colleagues for performing this RCT. Future studies with more focus on patients with HBeAg-positive status, viral relapse, hepatitis flares and hepatic decompensation following NUC cessation will help to address an ever-expanding clinical need. The Yunnan Science and Technology Department Fund (Grant No. 7012302106). The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. Yue-Meng Wan: conceptualization and manuscript draft. Hua-Mei Wu: conceptualization, supporting role in revision for important intellectual content. Song-Quan Huang: critical revision for important intellectual content, final approval. Yu-Hua Li: conceptualization, supporting role in revision for important intellectual content. Hong-Jing Yin: conceptualization, supporting role in revision for important intellectual content. The following are the supplementary data to this article: Download .pdf (.48 MB) Help with pdf files Multimedia component 1